Molecular dynamics simulation of metallothionein-drug complexes

The intermolecular interactions of metallothionein with nitrogen mustard dr ugs were studied by molecular dynamics simulations. Previous laboratory exp eriments have defined selective alkylation of two cysteine residues, and se lective binding was proposed to precede alkylation. The present study provi des information about accessibility to cysteines based on evaluating the in termolecular energies and distances in the first few ps of dynamics simulat ions. A series of dynamics simulations was performed with three drug molecu les positioned at the eight most solvent accessible cysteine residues of th e dimeric form of the protein. Sites proximal to the sulfhydryl groups of C ys-33 and Cys-48 were found to be the most favorable for complexing the azi ridinium forms of chlorambucil, melphalan, and mechlorethamine. The sites f or preferential binding are in qualitative agreement with the sites of sele ctive alkylation defined experimentally.